Exploration of treatments for subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) continues to be a leading cause of morbidity and mortality, with cerebral vasospasm as a common etiology of worse clinical progression. The purpose of this study was to evaluate and review the current literature concerning the effective treatment of SAH. The treatment options for SAH are expanding as new therapeutic targets are identified. Nimodipine is the primary medication prescribed due to its neuroprotective properties. In addition, certain drugs can enhance lymphatic flow and influence the recovery process, such as Dexmedetomidine, SSRIs, and DL-3-n-butylphthalide. Vasospastic and ischemic patients commonly undergo transluminal balloon angioplasty. Clinical trials have not yet provided conclusive evidence to support the use of magnesium or statins. Moreover, other agents such as calcium channel blockers, milrinone, hydrogen sulfide, exosomes, erythropoietin, cilostazol, fasudil, albumin, Eicosapentaenoic acid, corticosteroids, minocycline, and stellate ganglion blockade should be investigated further.


Introduction
Subarachnoid hemorrhage (SAH) is a complicated neurovascular condition with a high mortality and morbidity rate [1]. SAH affects many organ systems and the brain. Despite a steady decline in acute SAH mortality in the last decade, this condition still causes substantial morbidity and mortality [2]. Recovery after SAH can range from complete recovery to severe disability or death, primarily due to complications within the first two weeks of incidence [3]. Patients' clinical outcomes are determined by several factors, such as the severity of acute bleed, initial condition, early rebleeding, and delayed cerebral This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
ischemia [DCI]. Prognosis is also affected by cardiac and pulmonary complications [4]; however, consciousness level is considered the most critical early indicator [5].

Methods
A literature review on SAH was conducted using PubMed. The following search terms were used: subarachnoid hemorrhage (SAH), triple-H therapy, thrombolytic, calcium channel blocker, magnesium, milrinone, statins, endothelin receptor antagonists, fasudil, minocycline, Anti-inflammation, and Glymphatic System. In this review, we examined studies in English that investigated interventions for managing SAH.

Aneurysmal SAH
Intracranial aneurysms are not congenital and develop throughout life. The most common sites for saccular aneurysms are sites of arterial branching, commonly at the base of the brain, on the circle of Willis, or nearby it. There is a linear relationship between rupture risk and the size of the aneurysm [6]. Hypertension, smoking, and overconsumption of alcohol are modifiable risk factors for SAH [7]. In patients with aneurysmal SAH, rebleeding is associated with poor clinical outcomes and mortality; moreover, most rebleeding in aneurysmal subarachnoid bleeding occurs within 24 hours [8]. Because familial SAH accounts for only 10% of all episodes, multiple and large aneurysms are more likely to occur in sporadic cases than in domestic matters. In addition, patients with familial SAH have important genetic factors [9]. Aneurysms in the brain occur in approximately 10% of patients with autosomal dominant polycystic kidney disease [10]. In at least some patients, sudden increases in transmural arterial pressure may precipitate the rupture of an aneurysm. Exercise, sexual relations, and straining are reported to precede SAH in up to 20% of cases [11].

Non-aneurysmal SAH
In this usually benign SAH, the bleeding is restricted to the cisterns surrounding the midbrain. Usually, the hemorrhage centers anterior to the midbrain or the pons; however, in a few patients, blood can enter the quadrigeminal cistern [12]. There is no hemorrhage in the lateral Sylvian fissures or the anterior part of the interhemispheric fissure. Blood can sediment in the ventricular system, though if there is hemorrhage within the ventricular system or the brain parenchyma, another cause may be involved [13]. Shortor long-term rebleeding does not occur. There has been no evidence of delayed cerebral ischemia. A typical early complication is hydrocephalus [14]. Intracranial pressure (ICP) increases suddenly, which may reduce ongoing hemorrhage by reducing transmural tensions. However, it may also compromise cerebral blood flow [15].

Treatment
Three main neurological complications occur in the initial hours following hemorrhage: rebleeding, delayed brain ischemia, and hydrocephalus. Further, outcomes may also be adversely affected by several systemic complications. Aneurysm rupture results in a reduction of nitric oxide levels, increased fibrin aggregation, and hypercoagulability. Thus, microthrombi can form and contribute to DCI. Several therapies have been investigated to reduce complications and improve outcomes following SAH. Many remain controversial, and very few have been proven beneficial. The various treatments for SAH are discussed below.

Triple H therapy (HHH)
The triple H therapy consists of induced hypertension, hypervolemia, and hemodilution (HHH) to improve the body's oxygenation. HHH therapy has been a mainstay of treatment for SAH-induced vasospasm. In one study, HHH improved clinical examination in nearly 70% of patients with symptomatic vasospasm [16]. Another study of prophylactic HHH found that outcomes, blood volume, and symptoms did not improve at one year; in contrast, complications such as congestive heart failure and pneumonia were commonly seen [17]. Frontera and colleagues reported that patients who showed improved clinical outcomes within two hours of starting HHH therapy had lower mortality and disability rates [16].

Thrombolytics
In patients with aneurysmal SAH, cerebral vasospasm and infarction are the leading causes of morbidity and mortality [18]. Several factors contribute to cerebral infarction, including vasospasm, micro-thromboembolism, neuroinflammation, microvascular constriction, disruption of the blood-brain barrier, and diffuse cortical ischemia [19]. Due to its anticoagulant properties, heparin is commonly used to treat and prevent thromboembolism. There are numerous beneficial effects associated with heparin's pleiotropic development.
As it alters vasomotor regulations, it acts as an anti-inflammatory agent. Recent studies suggest it may also treat SAH-induced brain injury as a therapeutic inflammatory inhibitor [20]. Preclinical rodent models have shown that heparin reduces edema, inflammation, demyelination, and transsynaptic apoptosis [21].
Several studies have evaluated the efficacy of heparin and low molecular weight heparin (LMWH) infusions in SAH, but with contradictory results [22]. Wurm and colleagues, enoxaparin significantly reduced vasospasm and DCI and improved clinical outcomes over one month [22]. In contrast, Siironen and colleagues found no impact of enoxaparin on the outcome of SAH and a slight increase in intracranial hemorrhage [23]. In a metaanalysis, Patrick and colleagues demonstrated intravenous heparin's efficacy [24]. Further, unfractionated heparin administered intravenously for more than 48 hours was associated with a significant reduction in cerebral infarction in three studies involving 895 patients (odds ratio 0.44, 95% confidence interval 0.25-0.79) [24].

Calcium channel blockers
Calcium channel blockers (CCBs) have demonstrated improved outcomes and decreased risk of death and disability from vasospasm [25]. The primary mechanism of action in SAH is that CCBs can cross the blood-brain barrier and induce vasodilation. Nimodipine is a calcium antagonist prescribed to manage blood pressure. The first studies on nimodipine were conducted in patients with SAH to avoid vasospasm [26]. Moreover, it has been found that nimodipine improves neurological outcomes and reduces mortality among patients with SAH and is considered a standard of care due to its neuroprotective properties [27]. Oral nimodipine should be administered as soon as possible after SAH, typically at a dose of 60 mg every four hours for about 21 days, as recommended by the American Heart Association (AHA) and American Stroke Association (ASA) [28].
There are no precise mechanisms underlying these effects, thus, it is believed to be independent of the vasodilatory effects. A reduction in micro-thromboses, a key consequence of vasospasm and DCI, and resistance to calcium-mediated excitotoxicity are thought to be involved [27]. In terms of improving outcomes in SAH, only nimodipine has been approved by the Food and Drug Administration (FDA). In one study, it was reported that the use of nimodipine reduced the incidence of poor neurological effects by 40% [29]. Dayyani and colleagues conducted a meta-analysis on a comparison of nimodipine and placebo in 53 trials involving 10,415 patients, which suggested that nimodipine reduced all-cause mortality [30]. Furthermore, another study by Allen and colleagues of 125 SAH patients reported only 1 of 56 patients receiving nimodipine suffered from impaired neurological function or death compared to 8 out of 60 patients given a placebo (p=0.03) [31].
Nimodipine has also been found to reduce the incidence of DCI in SAH patients and to improve their prognosis. According to a meta-analysis of 16 trials evaluating calcium channel blockers in SAH, among 3,661 patients, the use of CCBs showed a significant reduction in poor outcomes and secondary ischemia after aneurysmal SAH, with oral nimodipine showing the highest benefits and the lowest risks; although, systemic hypotension was the most common complication [32].
Nicardipine, nitroprusside, and verapamil are other CCBs studied for treating vasospasm and DCI. Although they may have a role to play in treatment, their benefits are not as great as those of nimodipine [27]. For instance, after four months of nicardipine treatment, 49.5% of patients had significant reductions in vasospasm compared to 50.4% of patients who had received a placebo [33].

Magnesium
Voltage-dependent calcium channels are blocked by magnesium, which causes vasodilation of cerebral arteries. There is some evidence that magnesium may reduce DCI associated with intravenous magnesium infusion and secure glutamate release, providing a potential neuroprotective benefit [34]. In several clinical studies, magnesium was found to reduce cerebral vasospasm and improve neurological outcomes in SAH patients. It has been reported that intravenous magnesium has positive outcomes in animal studies and Phase II clinical trial data [35]. For example, in the phase II trial (MASH), 283 patients were randomized to continuously receive IV magnesium or placebo for 14 days after aneurysm treatment [34]. Three months after magnesium treatment, the risk of poor outcomes was reduced by 23%, and DCI was decreased by 34% [34]. This study concluded that magnesium might reduce the risk of DCI and, subsequently, poor outcomes [34]. In another randomized placebo-controlled phase III study, however, researchers found that 26.2% of patients receiving magnesium had poor outcomes compared to 25.3% of placebo patients [36]. According to the study, magnesium does not appear to contribute to better clinical outcomes in patients with SAH [36]. In contrast, in a meta-analysis that included 2035 patients, magnesium sulfate was ineffective as a prophylactic treatment for aneurysmal SAH [37].

Milrinone
Milrinone inhibits phosphodiesterase III, which hydrolyzes cyclic adenosine monophosphates (cAMP) and cyclic guanosine monophosphates (cGMP). In cardiac patient populations, milrinone has shown benefits in the augmentation of cardiac output and reduction of afterload. Still, it remains unclear how milrinone may be beneficial in treating DCI after SAH [38]. It has been proposed that milrinone may reduce vascular tone, thereby lessening cerebral vasospasms [39].
Milrinone was first described to be effective in treating cerebral vasospasm or DCI in 2001 through direct infusion into affected cerebral vessels [40,41]. In that study, there was a significant increase in middle cerebral artery diameter in M1 and M2 in all seven SAH patients with symptomatic angiographic cerebral vasospasm who received IA milrinone. 7 of 12 treatments with milrinone resulted in a gradual improvement in neurological symptoms a few hours after intra-arterial infusion [40]. Several studies have reported good results when milrinone is administered intra-arterially. This method of intra-arterial infusion of milrinone has been reported to have significant improvement in angiographic vasospasm [42]. Moreover, as a result of milrinone's anti-inflammatory properties, vascular smooth muscle proliferation and remodeling are inhibited in DCI patients [43].

Statins
Pyroptosis, inflammatory programmed cell death, unique to classical apoptosis and necrosis, has been reported to be prevalent in central nervous system diseases, including repair, aging, tumors, cerebral hemorrhages, and ischemic conditions [44,45]. A statin is an inhibitor of the enzyme MG-CoA reductase that lowers cholesterol; further, there is evidence that statins have anti-inflammatory, antiplatelet, and antioxidative effects, among others [46,47]. A study demonstrated that atorvastatin inhibits the autophagy signaling pathway to reduce early brain injury following SAH, alleviate cerebral vasospasm, mediate structural and functional remodeling of vascular endothelial cells, and alleviate brain edema by inhibiting Aquaporin 4 [AQP4]. expression [45]. As Wang and colleagues demonstrated, simvastatin has potential anticancer effects by inducing apoptosis through "NOD-like" receptor family pyrin domain containing 3 (NLRP3) -caspase 1 and interleukin-18 (IL-18) axis activation [48]. Moreover, a randomized phase II placebo-controlled study involving 14 days of either 40mg daily oral pravastatin or placebo in 80 patients with SAH showed a 32% reduction in vasospasm (p=0.006) and 42% reduction in severe vasospasm (p= 0.044) in pravastatintreated patients [47].

Endothelin receptor antagonists
Endothelin receptor antagonists are drugs that stop one from binding to its receptors and inhibit the constrictive effects of endothelin on the smooth muscles of the vascular system. Vasospasm is associated with the overproduction of endothelin in SAH [49]. There has been much research on clozasentan as an endothelin receptor antagonist in SAH. In a phase II trial (CONSCIOUS), 65% of patients in the clazosentan group showed dose-dependent risk reductions in angiographic vasospasm [50]; further, these results were further supported in another study providing evidence for reversal of established vasospasm within 48 hours of treatment [51]. In contrast, in another open-label, placebo-controlled, prospective, doubleblinded, phase III trial (CONSCIOUS2) there was no statistically significant improvement in clinical outcomes in the clazosentan group (728/1157 patients, 5mg/hr) [52]. There was, however, a significant reduction in all-cause mortality, vasospasm-related infarction, rescue therapy for vasospasm with clazosentan, and DCI, compared to placebo (p=0.01) [52].

Fasudil
Several new therapeutic approaches are being developed to target Rho kinase (ROCK) in neurodegenerative disorders. Two ROCK proteins exist; ROCK1, mainly expressed in peripheral tissues and ROCK2, found in the central nervous system. Axonal degeneration and impaired axonal regeneration are the consequences of axonal growth inhibitory molecules binding to specific extracellular receptors [53,54]. Fasudil is a Rho-kinase inhibitor that dilates blood vessels. There is evidence that Rho-kinase is involved in mechanisms that cause vasoconstriction, inflammation, endothelial damage, and reactive oxygen species [55]. As part of a phase III trial, Fasudil markedly improved clinical results in patients with acute ischemic stroke treated with Fasudil [56]. Although Fasudil is only licensed for intravenous administration in Japan, oral formulations have been tested in humans, including extended-release capsules. Humans have been exposed to Fasudil for 8 and 12 weeks for treatment of angina pectoris and pulmonary arterial hypertension [57]. In a study by Shibuya and colleagues, 14 days of Fasudil treatment revealed decreased angiographic vasospasm by 38% (p=0.0023) and symptomatic vasospasm by 30% (p= 0.0247), compared to placebo [58].

Glymphatic clearance
Only the central nervous system (CNS) lacks well-defined lymphatic vessels to help eliminate metabolic waste products from the interstitial space [59]. The CNS is more difficult to define than peripheral systems regarding venous and lymphatic outflow. Approximately 500cc of CSF secreted by the choroid plexus is reabsorbed by arachnoid granulations (AG) and parenchymal lymphatic channels [60]. An AG is a protrusion of the arachnoid mater into the dural venous sinus that facilitates the reabsorption of CSF. CSF, the lymphatic outflow via dural intravascular channels, is mediated by AG subsets [61]. Additionally, it has been shown that the Glymphatic system (GS) regulates the distribution of lipids, amino acids, glucose, and neuromodulators throughout the brain [62].

Dexmedetomidine
Sedative anesthetics were one of the first drugs to be shown to enhance glymphatic flow, replicating natural sleep's effects on brain metabolite clearance [63]. As a selective beta-2 agonist, dexmedetomidine (Dex) is a relatively new drug prescribed as a sedative during surgery. Dex has been shown to possess anti-inflammatory and antioxidant properties in numerous studies that have been conducted [64]. In rodent models of SAH, Dex reduces neurological deficits and attenuates early brain injury [65,66]. Recent studies suggest that Dex enhances the glymphatic delivery of opioids and anesthetics co-administered to rodents [67]. Through enhanced lymphatic efflux, drugs are delivered from CSF to ISF, facilitating brain drug exposure [68]. In a study by Lilius and colleagues, mice treated with Dex and naloxone had higher peak concentrations of oxycodone and naloxone throughout their ISFs; during this study, naloxone concentrations in hippocampal, thalamic, and hypothalamic peaked immediately after administration and declined after 30 minutes, while naloxone concentrations in mice treated with Dex were significantly elevated following thirty minutes and remained high for two hours [69].

DL-3-n-butylphthalide
Neurodegenerative disorders, cerebrovascular diseases, and Parkinson's disease have been studied as potential therapeutic targets for DL-3-n-butylphthalide (DL-NBP) [70]. These diseases are associated with multiple pathophysiological processes, such as inflammation, free radicals, thrombogenesis, neuronal apoptosis, and mitochondrial dysfunction. The effects of DL-NBP on GC and amyloid deposition were demonstrated in transgenic mice models of Alzheimer's disease [71]. This study showed an increase in perivascular AQP4 expression after DL-NBP administration. As a result of the long-term administration of DL-NBP, AQP4 expression was shown to increase in AD models, conferring vascular and neuroprotection in both situations [72].

SSRI
The SSRI fluoxetine is widely used to treat depression with its selective serotonin reuptake inhibitor properties. Additionally, it may reduce early brain injury after SAH and improve cognitive function after long-term use in patients with vascular dementia and Alzheimer's disease [73]. Apoptosis and inflammation are both attenuated by fluoxetine in SAH rodent models. A recent study suggests Fluoxetine may ameliorate neurological disorders, including SAH, by affecting lymphatic flow, specifically AQP4 in astrocytes [74]. In particular, it affects the function of AQP4 on astrocytes and cerebrovascular autoregulation. Studies have shown that chronic stress reduces AQP4 expression in mice with depression [74]. Further, it is known that fluoxetine selectively increases cerebral blood flow, negating the effect of norepinephrine when combined with it [75]. A key regulator of lymphatic flow, the cerebrovascular system, appears to be affected by fluoxetine via interference of calcium signaling. The long-term use of fluoxetine has been studied, which makes it more feasible to follow it up after SAH, even though it does not have the potentially adverse hemodynamic effects of Dex and nimodipine [76].

Conclusion
Treatment options for SAH are constantly evolving. Vasospasm and DCI contribute significantly to morbidity and mortality associated with SAH. Despite its neuroprotective properties and improved clinical outcomes, oral nimodipine remains the primary medication routinely used in practice. Numerous studies have examined other medical treatments and interventions for SAH, particularly those that prevent and treat vasospasm. The use of many of these treatments has crossed over into clinical practice. An increase in morbidity and mortality is associated with early brain injury in SAH. There is still a lot to be explored in this area. Further trials are necessary to determine if experimental drugs can effectively treat SAH, early brain injury, and vasospasm.   The glymphatic pathway in the brain parenchyma is responsible for the circulation of CSF and ISF.